IN-VITRO STUDIES OF TAXOL AS A RADIATION SENSITIZER IN HUMAN TUMOR-CELLS

Background: Cells exposed to paclitaxel (Taxol) develop a cell cycle arrest in G(2)/M. It has long been recognized that late G(2) and M are the most radiosensitive phases of the cell cycle. Purpose: These studies were performed to assess the in vitro radiosensitization properties of paclitaxel in human tumor cell lines. Methods: The effect of paclitaxel at concentrations ranging from 0 to 10000 nM on the radiation sensitivity (from 0 to as much as 10 Gy in certain experiments) of human breast (MCF-7), lung (A549), ovary (OVG-1), and pancreas (PC-Sh) adenocarcinoma cells was determined using clonogenic assays. DNA flow cytometry studies were performed to define the cell cycle characteristics of populations of cells that had been treated for 6-72 hours with 0, 100, 1000, or 10000 nM paclitaxel. Results: All cell lines developed a G(2)/M block after exposure to 100-10000 nM paclitaxel for 24 hours. However, the degree of radiosensitization produced by paclitaxel varied among the cell lines. The sensitizer enhancement ratio (SER) of paclitaxel at 10% survival was 1.8 in MCF-7 cells and 1.6 in OVG-1 cells. However, paclitaxel at any concentration was unable to enhance the radiation sensitivity of A549 cells. PC-Sh cells demonstrated a complex and inconsistent radiosensitization response to paclitaxel. At 10% survival, an SER of 1.5 was observed in PC-Sh cells. However, at 1% survival, no radiosensitization was observed in PC-Sh cells. Maneuvers that prevented paclitaxel from producing a G(2)/M block, including coincident treatment with cycloheximide or treatment of cells in plateau phase of growth, completely abrogated the radiosensitization afforded by paclitaxel in MCF-7 cells. Conclusions: Paclitaxel is a modest radiosensitizer in some, but not all, humor tumor cells. The degree of radiosensitization that we have observed with paclitaxel is similar to what has been found with other chemotherapeutic agents. The absence of radiosensitization by paclitaxel in MCF-7 cells grown to plateau phase or treated with cycloheximide implies that the development of a G(2)/M block is a necessary condition for paclitaxel radiosensitization. However, the inability of paclitaxel to radiosensitize A549 cells despite the presence of a G(2)/M block in those cells demonstrates that a G(2)/M block is not a sufficient condition for paclitaxel radiosensitization. Implications: Paclitaxel can radiosensitize to a modest degree some, but not all, human cell lines by a mechanism that requires the production of a G(2)/M cell cycle block. Additional studies are needed to define more clearly the mechanism by which paclitaxel radiosensitizes cells.